Assessment of Tumor Markers in Renal Transplant Recipients.

Background/Aim: Malignant tumors are diagnosed using various methods, including diagnostic imaging methods. The measurement of tumor markers is commonly used because of its noninvasiveness and convenience. Furthermore, it is known that the excretion and metabolism of some tumor markers are affected by impaired renal function. In the present study, we investigated the effect of improved renal function on pre-and post-transplantation changes in tumor marker levels [carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and prostate-specific antigen (PSA)] in renal transplant recipients. Patients and Methods: A total of 116 renal transplant recipients, who had not been diagnosed with malignancies between January 2012 and December 2019, were included, and tumor markers were investigated. Results: CEA showed a significant decrease after kidney transplantation, regardless of the dialysis type (3.6→2.6 ng/ml, p<0.001), while other tumor markers showed a significant increase (AFP: 3.6→3.7 ng/ml; CA19-9: 16.2→19.5 U/ml; PSA: 0.95→1.05 ng/ml; all p<0.05). Pre- and postoperative eGFR ratios and postoperative liver function were identified as factors influencing the postoperative CEA and CA19-9 values, while PSA was influenced by the duration of dialysis. No statistically significant factors were found for AFP levels. Conclusion: Caution should be exercised when investigating tumor markers in patients with renal dysfunction, as tumor marker levels may vary depending on the pathophysiology of each patient.

Remarkable improvement of diabetic nephropathy in transplanted allograft after kidney transplantation.

Although glomerular damage caused by diabetic nephropathy was thought to be irre-versible, in recent years, there have been reports on improvement in glomerular damage with strict glycemic control. However, few reports are available on the pathologic course after renal transplantation of donor-derived grafts with findings of diabetic nephropathy. A 53-year-old woman underwent an ABO blood-type compatible living-donor renal transplant. The recipient had no history of diabetes, and fasting blood glucose and hemo-globin A1c (HbA1c) levels were both normal. The donor was a 57-year-old male who had received treatment for type 2 diabetes mellitus for 10 years. Transplant renal biopsy performed 1 h after revascularization showed mesangial matrix expansion and arterial hyalinosis due to diabetic nephropathy. The blood glucose level was within the normal range after transplantation. Mesangial matrix expansion and arterial hyalinosis disap-peared in allograft biopsy samples 7 years after transplantation. We observed significant improvement in the pathological findings of donor-derived diabetic nephropathy after renal transplantation in the subsequent follow-ups.

A retroperitoneal primary undifferentiated pleomorphic sarcoma.

A 52-year-old male had pain in the right back and right hypochondrium, and an abdominal CT scan revealed a 49-mm tumor in the right upper perirenal space. Additional MRI and PET-CT suggested that the tumor may be a primary adrenal carcinoma and could invade the liver and diaphragmatic leg. The tumor was completely removed by laparotomy and histopathologically diagnosed as retroperitoneal primary undifferentiated pleomorphic sarcoma. The patient has remained recurrence-free for 1.5 years after the surgery.

D-Asparagine is an Ideal Endogenous Molecule for Measuring the Glomerular Filtration Rate.

Introduction: An ideal endogenous molecule for measuring glomerular filtration rate (GFR) is still unknown. However, a rare enantiomer of serine, d-serine, is useful in GFR measurement. This study explored the potential of other d-amino acids for kidney function assessment. Methods: This was a cross-sectional observational study of 207 living kidney transplant donors and recipients, for whom GFR was measured using clearance of inulin (C-in). Associations between levels of d-amino acids and GFR were analyzed using multivariate factor analysis. Fractional excretion (FE), a ratio of the clearance of a substance to C-in as a standard molecule, was calculated to monitor the excretion ratio after glomerular filtration. Dissociation from an ideal FE of 100% was assessed as a bias. Proportional bias against C-in was calculated using Deming regression. Results: Multivariate analysis identified the blood level of d-asparagine to reflect GFR. Means of blood d-asparagine and clearance of d-asparagine (C-d-Asn) were 0.21 µM and 65.0 ml/min per 1.73 m2, respectively. Inulin-based FE (FEin) of d-asparagine was 98.67% (95% confidence interval [CI]: 96.43-100.90%) and less biased than those of known GFR markers, such as FEin of creatinine (147.93 [145.39-150.46]; P < 0.001) and d-serine (84.84 [83.22-86.46]; P < 0.001). A proportional bias of C-d-Asn to C-in was -7.8% (95% CI, -14.5 to -0.6%), which was minor compared to those of clearance of creatinine (-34.5% [-37.9 to -31.0%]) and d-serine (21.2% [13.9-28.9]). Conclusion: D-Asparagine acts similar to inulin in the kidney. Therefore, d-asparagine is an ideal endogenous molecule that can be used for GFR measurement.

A Case Report of a Kidney Transplant Recipient With Organizing Pneumonia After Graft Loss.

We present a case of a 68-year-old male patient who underwent ABO-incompatible living kidney transplantation from his wife because of immunoglobulin A nephropathy 13 years ago. Over time, the patient showed a gradual decline in graft function and required reinitiation of hemodialysis because of fluid overload, which led to his admission to our hospital. An arteriovenous fistula was created, and subsequently, hemodialysis therapy was started. Because he had chronic cytomegalovirus retinopathy and thrombotic microangiopathy due to immunosuppressive therapy at admission, mycophenolate mofetil and tacrolimus were discontinued during hemodialysis initiation. Only low-dose prednisolone was continued. One week later, the patient had a fever, and chest computed tomography revealed bilateral pneumonia, which was not improved by antibiotics. The patient was diagnosed with organized pneumonia. After ruling out opportunistic infection, including pneumocystis pneumonia, increased doses of prednisolone resulted in the remission of organizing pneumonia.

Seronegative rheumatoid arthritis after combination therapy with ipilimumab and nivolumab for postoperative pancreatic and liver metastases from renal cell carcinoma.

Introduction: Since the approval of immune checkpoint inhibitors for renal cell carcinoma treatment, therapeutic efficacy has been enhanced. However, although autoimmune-related side effects may occur, rheumatoid immune-related adverse events seldom develop. Case presentation: A 78-year-old Japanese man with renal cell carcinoma developed pancreatic and liver metastases after bilateral partial nephrectomy and was treated with ipilimumab and nivolumab. After 22 months, he developed arthralgia in limbs and knee joints, accompanied by limb swelling. The diagnosis was seronegative rheumatoid arthritis. Nivolumab was discontinued, and prednisolone was initiated, quickly improving symptoms. Although nivolumab was resumed after 2 months, arthritis did not recur. Conclusion: Immune checkpoint inhibitors may cause a wide variety of immune-related adverse events. When arthritis is encountered during immune checkpoint inhibitor administration, seronegative rheumatoid arthritis should be differentiated from other types of arthritis, despite being less frequent.

Single-cell transcriptome analysis of a rat model of bilateral renal ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) causes massive tissue damage. Renal IRI is the most common type of acute renal injury, and the defects caused by it may progress to chronic kidney disease (CKD). Rodent models of renal IRI, with various patterns, have been used to study the treatment of human kidney injury. A rat model of bilateral IRI, in which the bilateral kidney blood vessels are clamped for 60 min, is widely used, inducing both acute and chronic kidney disease. However, the molecular mechanisms underlying the effects of bilateral IRI on kidney cells have not yet been fully elucidated. This study aimed to perform a whole-transcriptome analysis of the IRI kidney using single-cell RNA sequencing. We found renal parenchymal cells, including those from the proximal tubule, the loop of Henle, and distal tubules, to be damaged by IRI. In addition, we observed significant changes in macrophage population. Our study delineated the detailed cellular and molecular changes that occur in the rat model of bilateral IRI. Collectively, our data and analyses provided a foundation for understanding IRI-related kidney diseases in rat models.

Remitting seronegative symmetrical synovitis with pitting edema syndrome induced by pembrolizumab in patient with urothelial carcinoma.

Introduction: Recent introduction of immuno-oncology drugs such as pembrolizumab has resulted in improved outcomes for urothelial carcinoma patients. However, immune-related adverse events generally show great variance and are often difficult to diagnose and control. Case presentation: An 84-year-old Japanese male with urothelial carcinoma metastasis to the lungs after a laparoscopic left radical nephroureterectomy procedure was treated with pembrolizumab, an immuno-oncology drug, as second-line therapy. At week 6, inflammatory arthralgia involving the hands and shoulder joints, and edema of the hands were presented. The diagnosis was remitting seronegative symmetrical synovitis with pitting edema syndrome. Pembrolizumab was discontinued, and oral corticosteroid therapy was started. Two months later, pembrolizumab treatment was resumed because of a significant improvement in patient condition. Conclusion: Although rare, immune-related adverse events are occasionally encountered during the use of immune-oncology drugs; thus, early diagnosis and appropriate treatment are important.

Everolimus Reduces Cancer Incidence and Improves Patient and Graft Survival Rates after Kidney Transplantation: A Multi-Center Study.

Kidney transplantation can prevent renal failure and associated complications in patients with end-stage renal disease. Despite the good quality of life, de novo cancers after kidney transplantation are a major complication impacting survival and there is an urgent need to establish immunosuppressive protocols to prevent de novo cancers. We conducted a multi-center retrospective study of 2002 patients who underwent kidney transplantation between 1965 and 2020 to examine patient and graft survival rates and cumulative cancer incidence in the following groups categorized based on specific induction immunosuppressive therapies: group 1, antiproliferative agents and steroids; group 2, calcineurin inhibitors (CNIs), antiproliferative agents and steroids; group 3, CNIs, mycophenolate mofetil, and steroids; and group 4, mammalian target of rapamycin inhibitors including everolimus, CNIs, mycophenolate mofetil, and steroids. The patient and graft survival rates were significantly higher in groups 3 and 4. The cumulative cancer incidence rate significantly increased with the use of more potent immunosuppressants, and the time to develop cancer was shorter. Only one patient in group 4 developed de novo cancer. Potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Our data also suggest that everolimus might suppress cancer development after kidney transplantation.

A study of the mechanisms responsible for the action of new immunosuppressants and their effects on rat small intestinal transplantation.

In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.

Incidence and mortality of post-transplant lymphoproliferative disorders after kidney transplantation: A real-world retrospective analysis in Japan.

OBJECTIVES: Post-transplant lymphoproliferative disorder is a potentially life-threatening complication that has a greater risk of occurrence in the setting of immunosuppression and oncogenic viral infections after transplant surgery. Few studies have reported the cumulative incidence, histological subtypes and clinical outcomes of this disorder in kidney transplant recipients. METHODS: We retrospectively investigated 34 post-transplant lymphoproliferative disorder patients diagnosed out of the 1210 kidney transplant recipients who had undergone the surgery at the two largest centers in Japan between January 1983 and December 2017. RESULTS: A total of 32 patients (94.1%) developed late-onset post-transplant lymphoproliferative disorder (diagnosed 1 year after transplantation). The cumulative incidence rates were 0.76% and 1.59% at 5 and 10 years post-transplantation, respectively. The central nervous system was the most common site (35.3%, 12/34). Overall survival was similar between patients with and without central nervous system lesions (P = 0.676). Of all of the cases, 23.5% (8/34) were detected through cancer screening. Importantly, patients with screening-detected post-transplant lymphoproliferative disorder had better overall survival than those with the disorder who had been symptom detected (P = 0.0215). Overall survival was significantly reduced in patients who developed the disorder compared with those who did not (P = 0.0001). CONCLUSIONS: Post-transplant lymphoproliferative disorder was more likely to occur in the late post-transplantation period, which showed that long-term medical examination for transplant recipients is required. Based on our findings, we propose vigilant, long-term, cancer screening in kidney transplant recipients.

Rapid deterioration of renal function following coronavirus disease 2019 in a renal transplant recipient.

Introduction: The coronavirus disease 2019 pandemic emerged in December 2019. Renal transplant recipients receiving chronic immunosuppression are considered to be at a high risk of infection. Aside from upper respiratory tract symptoms, coronavirus disease 2019 has also been reported to cause acute kidney injury in 20-50% of infected cases. Case presentation: A 62-year-old male renal transplant recipient presented with high fever, diarrhea, and cough, concurrent with rapid deterioration of graft function. The patient tested positive for coronavirus disease 2019. The pathological findings of the graft biopsy revealed diffuse flattening of tubular epithelial cells and extensive loss of the brush border in proximal tubular cells. Mycophenolate mofetil was discontinued and sotrovimab, remdesivir, intravenous immunoglobulin, and intravenous methylprednisolone were administered, resulting in gradual improvements in clinical symptoms and renal function. Conclusion: We describe a case of a coronavirus disease 2019-infected kidney transplant recipient who developed severe acute kidney injury caused by severe acute tubular necrosis.

[A Case of Remission of Metastatic Germ Cell Tumor in an Elderly Patient by Multimodal Treatment].

There have been few reports of multimodal treatment such as chemotherapy and surgical resection for testicular tumors over 40 years old. In this case, a 64-year-old man with nonseminoma, pT2N2M1aS1, stage IIIb, IGCCC good prognosis completed induction chemotherapy, followed by retroperitoneal lymph node dissection and resection of lung metastases. Chemotherapy (4 courses of etoposide and cisplatin therapy) was completed without serious adverse events other than grade 4 neutropenia. Resection of the residual tumor confirmed no viable tumor cells. There was no evidence of recurrence or elevation of tumor markers in the following 6 months. Similar cases could increase with the increase of testicular tumors in the elderly.

[Ectopic Ureterocele of Adult Male with Urination Difficulty : A Case Report].

Ectopic ureteroceles is sometimes noted in children as an incidental finding in antenatal ultrasonography results or because of symptoms related to a urinary tract infection. In contrast, it is rarely noted in adults, with only 18 cases in Japan presented in literature. We report here a 30-year-old adult male with an ectopic ureterocele discovered due to urination difficulty. The patient noted a poor urine stream and macroscopic hematuria after exercise, and over time needed manual compression on the lower abdomen for urination. Computed tomography results revealed a 35 mm right ureterocele containing a 7.0 mm stone. Cystoscopy showed the ureterocele protruding into the prostatic urethra, which was thought to be the cause of urination difficulty. Transurethral resection of the ureterocele and lithotripsy for the stone were performed. The right ureteral orifice was not visualized during the operation. Resection was performed from the bladder neck side so that the ureterocele wall did not interfere with urination and the calculus was crushed with a pneumatic lithotripter (LithoClast®). Urination difficulty was improved following the procedures. Urinary cystourethrography performed two weeks postoperatively confirmed no vesicoureteral reflux. No symptoms of dysuria or fever were noted at a follow-up visit two months after the operation.

Perirenal fat metastasis of prostate cancer.

A 72-year-old male underwent an abdominal CT scan, which revealed a 17-mm nodular incidentaloma in fat tissue in the left perirenal space. Retroperitoneoscopic surgery was performed to remove the tumor and histopathological results revealed a PSA-positive adenocarcinoma, which was diagnosed as a metastatic lesion associated with prostate cancer. PSA was high at 30.083 ng/ml and MRI findings showed extracapsular extension of prostate cancer in the left peripheral zone of the prostate gland. Biopsy results with a Gleason score of 4 + 4 confirmed the diagnosis of prostate cancer. The case was diagnosed as prostate cancer metastasis in perirenal fat tissue.

[OUTCOMES OF BLADDER CANCER IN NONAGENARIANS].

(Objectives) We evaluated the chronological change in the number and proportion of elderly patients with bladder cancer. We also retrospectively investigated the clinical outcomes of bladder cancer in patients of ≥90 years of age. (Patients and methods) We evaluated the chronological change in the number and proportion of patients of ≥90 years of age who were clinically diagnosed with bladder cancer and who underwent transurethral resection of a bladder tumor (TUR-BT) at our hospital between 2008 and 2018. We also assessed the clinicopathological factors, perioperative outcomes, and clinical outcomes in bladder cancer patients of ≥90 years of age. (Results) The number and proportion of bladder cancer patients of ≥90 years of age increased with time. A total of 39 patients of ≥90 years of age underwent TUR-BT at our hospital, among whom 22 were diagnosed with primary bladder cancer. The median age was 91 years. No grade ≥III complications were observed after TUR-BT. Two out of 6 with pT1 disease underwent second TUR-BT. Two out of 7 with pT1 disease or carcinoma in situ received intravesical BCG therapy. Six deaths were observed during the study period, 2 of which were due to bladder cancer. At 1 and 3 years after TUR-BT, the overall survival rates of the 22 patients were 80.4% and 68.9%, respectively. (Conclusions) The number and proportion of elderly patients with bladder cancer increased with time. The current standard of care including second TUR-BT and intravesical BCG therapy for high-risk non-muscle invasive bladder cancer was underutilized in nonagenarians.

Cumulative cancer incidence and mortality after kidney transplantation in Japan: A long-term multicenter cohort study.

Kidney transplantation is the most promising treatment to improve mortality and life quality in end-stage kidney disease; however, cancer remains a leading cause of death. Several factors including immunosuppressants might be associated with a gradual increase in cumulative cancer incidence after kidney transplantation. Risk factors for cancer and overall and cancer-specific survival were analyzed in 1973 kidney transplant recipients from three study institutions in Japan. The 5-, 10-, 20-, and 30-year overall and cancer-specific survival rates were 93.3%, 88.4%, 78.0%, and 63.6% and 99.4%, 98.0%, 95.3%, and 91.7%, respectively. The overall survival rate was significantly higher and the graft survival rate was significantly lower in recipients without cancer than in those with cancer. Older recipient age, longer dialysis duration before kidney transplantation, and history of transfusion were significant predictors of cancer. Dialysis duration before kidney transplantation was a prognostic factor of overall survival rate. Regarding cancer-specific survival rates, older recipient age and dialysis duration before kidney transplantation were prognostic factors of worse cancer-specific survival rates. The type of immunosuppressant was not associated with an increased cancer rate. Aggressiveness of immunosuppressant regimens or potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Older age and longer dialysis duration before kidney transplantation were risk factors of cancer-specific survival rate.

Implementation of repeat biopsy and detection of cancer after a diagnosis of atypical small acinar proliferation of the prostate.

Current guidelines recommend a repeat biopsy within 3-6 months after an initial diagnosis of atypical small acinar proliferation (ASAP) due to the high incidence of cancer detection on repeat biopsy. The current study sought to investigate practice patterns after a diagnosis of ASAP in a real-world setting and examine the clinicopathological outcomes of repeat biopsy. The departmental database of the Hyogo Prefectural Nishinomiya Hospital identified 97 of 1,218 patients with a diagnosis of ASAP on initial biopsy from 2011 to 2016. Clinical and pathological data were retrospectively analyzed. Of the 97 patients, 34 (35.1%) underwent a repeat biopsy. Patients with a repeat biopsy had a significantly higher prostate-specific antigen (PSA) velocity and shorter PSA doubling time than patients without a repeat biopsy (P=0.0002), and of these 34 patients with a repeat biopsy, 16 (47.1%) were diagnosed as having cancer. Multivariate logistic regression analysis revealed that a small prostate (P=0.0250) and advanced age (P=0.0297) were associated with cancer detection on repeat biopsy. Of the 16 cancers identified, 13 (81.6%) were diagnosed with a Gleason score >6. The results indicated that the implementation of a repeat biopsy for patients with ASAP could be affected by clinical characteristics in real-world settings, despite the current recommendation of guidelines endorsing immediate repeat biopsy. Prostate volume and age would aid in the decision-making process to perform repeat biopsy in patients with high PSA velocity and short PSA doubling time after a diagnosis of ASAP.

Metastatic bladder tumor from prostate cancer causing a ball valve-like obstruction in urination.

We report a rare case of prostate cancer that apparently metastasized to the bladder and formed a pedunculated mass that caused a ball valve-like obstruction in urination. A 57-year-old man with metastatic prostate cancer was referred to the emergency department for acute urinary retention. Cystoscopy and magnetic resonance imaging revealed a pedunculated mass measuring approximately 2 cm in size in the bladder neck that appeared to cause urinary obstruction in a ball valve-like manner. Transurethral resection of the bladder tumor was performed that resolved his symptom, and histopathological findings confirmed a diagnosis of poorly differentiated prostate adenocarcinoma.

Primary perirenal angiosarcoma: A preoperative diagnostic challenge.

Angiosarcoma arising in the retroperitoneal space is rare. We report a case of perirenal angiosarcoma presenting preoperative diagnostic difficulties. A 49-year-old man was referred to our department with left kidney mass. Specimens of CT-guided percutaneous needle biopsy of the mass did not contain any atypical cells suggestive of malignancy. A CT scan 6 months after embolization of the tumor revealed growth of the mass and two space-occupying lesions appearing in the liver. Laparoscopic resection of the left kidney with perirenal mass and one of the liver lesions was performed. Histopathological findings confirmed a diagnosis of perirenal angiosarcoma with hepatic metastases.